Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03832712 |
| Other study ID # |
2017-238-31 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 30, 2018 |
| Est. completion date |
January 30, 2027 |
Study information
| Verified date |
May 2022 |
| Source |
Karolinska Institutet |
| Contact |
Anne-Louice Eriksson |
| Phone |
+468907850000 |
| Email |
annelouice.eriksson[@]vll.se |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment in essential
tremor (ET) in a randomized, single-blinded controlled trial.
Description:
PURPOSE AND AIMS
- Aim 1 - To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment
in essential tremor (ET) in a randomized, single-blinded controlled trial.
- Aim 2 - To compare the effect of DBS in the established target in the ventrolateral
(VL)-thalamus/ nucleus ventralis intermedius thalami (Vim) and in a new target in the
posterior subthalamic area (PSA)/caudal Zona incerta (cZi).
- Aim 3 - To map the target area in the VL-thalamus and PSA concerning effects and side
effects of stimulation in order to identify and delineate the optimal target.
- Aim 4 - To evaluate the long-term effects of DBS for ET in a longitudinal non-randomized
evaluation.
SURVEY OF THE FIELD Deep Brain Stimulation (DBS) In DBS, thin quadripolar electrode leads
(with four 1.5 mm long and 1.27 mm thick contacts, separated by 1.5 mm space), connected to a
neuropacemaker are implanted with stereotactic technique into the central parts of the brain
where the neuronal activity is modulated with electrical current. DBS has revolutionized the
treatment of Parkinson´s disease and other movement disorders, and more than 150.000 patients
have so far been operated. Currently, new indications and targets are emerging.
However, many of the brain targets subjected for DBS are not well defined, and one of the
main problem with DBS is likely to be the high number of suboptimal placed electrodes with
lack of effect, unacceptable side effects and costly revisions. Further, even though this is
an invasive and highly resource demanding therapy, most clinical indications for DBS (asides
from Parkinson´s disease and dystonia) are not evidence based. They are considered as
"established treatments" and often provided as clinical treatment and not within the context
of trials or scientific studies.
DBS for Essential Tremor ET is the most common adult movement disorder with a prevalence of
about 5% in the population above 65 years of age. Of patients who seek medical care up to 50%
do not respond adequately to drug therapy.
The thalamic nucleus ventralis intermedius (Vim) is the projection structure of the
cerebello-thalamic fibers mediating tremor. Hence, Vim has been an "established" target for
surgical treatment of ET during the thalamotomy era, and when DBS was introduced and replaced
thalamotomy, the Vim was logically the target for DBS for tremor. However, data from recent
years indicate that it might not be stimulation of the Vim itself, but rather, the
stimulation was affecting the pathologic tremor oscillations mediated by the
cerebello-thalamic-cortical projections, located in the PSA and the caudal zona incerta
(cZi). Thus, a number of studies have demonstrated that electrode contacts that reach the PSA
have a better effect on tremor than those located more dorsally-rostrally in the Vim. This
subthalamic area, which is situated immediately ventral-caudal to the Vim, is particularly
dense with cerebello-thalamic axons, dispersing into the Vim. Stimulation is thus likely to
involve more axons in the PSA than in the Vim, since these axons in the PSA constitute so to
speak a bottle neck of the axonal traffic mediating tremor. It is also plausible that
stimulation of axons rather than stimulation of nuclei actually affects by antidromic and
orthodromic propagation more neurons and therefore also alters tremor oscillations more
efficiently. A number of studies directly targeting the cZi have also recently presented
results comparing favorably with the results published for Vim DBS.
Level of evidence regarding DBS in ET:
Neither the Vim nor the cZi are evidence based targets, and there are no evidence-based DBS
procedures for ET (level IV evidence only), even though this is the second most common
indication for DBS. However, the Vim is by tradition the established target for ET and the
procedure is recommended in the Swedish guidelines for treatment of tremor.
The results of Vim DBS ET have been demonstrated in a number of uncontrolled, mostly minor
studies. A problem is that many of these studies are likely to contain electrodes placed
blindly within the PSA36 and that the actual location of the active electrode contacts of the
DBS lead is seldom taken into consideration. Further, many reports lack a preoperative
baseline and the results are often reported in a heterogeneous manner, making comparison
between different studies difficult. Regarding cZi DBS, excluding our own studies, the
results of cZi DBS in 33 patients have been presented in five small and non-randomized
studies. Concerning the relative merits of the two targets, we have previously presented a
tremor reduction of 86 % following cZi, compared to only 60% in the Vim4, and demonstrated
that the electrode contacts with the best effect in what was called Vim were often placed in
the PSA. There is further a scarcity of long-term data regarding both targets.
Identifying the brain target in the individual patient In a recent study of 28 000
procedures, electrode revisions constituted up to one third of all DBS procedures. It is
likely that misplaced electrodes due to difficulties in identifying the target is one of the
major causes explaining a poor result in DBS for movement disorders.
There are a number of different ways in which the target can be identified. Even for brain
targets that can be visually identified on MRI, some centers rely mostly on statistical
coordinates of the targets based on anatomical atlases, but this may result in poorly placed
electrodes, due to significant inter-individual differences in the anatomy. However,
concerning the Vim, identification of that target in relation to ventricular landmarks is a
necessity since the Vim cannot be visualized as such in MRI.
Currently, 60 % of the centers are relying on micro-electrode recording (MER) in order to
identify the target in the individual patient. This is an invasive neurophysiological method
necessitating considerable resources. It is also associated with an increased risk of
hemorrhages, since it involves introducing several sharp cannulas and electrodes into the
target area. The third method is visual anatomical targeting, whereby the target is
identified on the patients´ MRI, either directly or in relation to visible very closely
related landmarks (Figure 2). We have over the years made significant contributions in the
development of this last method, both concerning the pallidum, STN and cZi. Unfortunately
this method demands a high level of dedication and relies to a high degree on personal
experience. Scientifically based guidelines delineating the target areas and identifying the
optimal target do not readily exist.
Common for all different methods is that it is normally required that the patient is awake
during surgery in order to allow for intra-operative testing of effect/side effects, even if
some today perform the procedure in general anesthesia concerning some of the targets. If the
brain targets could be identified with a high degree of certainty, and the electrode position
within that target can be verified during surgery, then having the patients awake during
surgery would no longer be necessary.
Identifying and delineating the optimal targets The literature regarding optimal target
point/volume for the different targets is surprisingly meagre. The most common target, the
subthalamic nucleus (STN), is also the most studied regarding this issue, but the effect has
been evaluated in relation to the location of the electrode in no more than 260 patients in a
total of 13 different studies. Interestingly, most of these studies have found that the best
effect is not achieved in the target structure itself, but in another adjacent structure, the
more rostral part of the Zona incerta overlying the STN. The same is true regarding the few
studies of thalamic surgery for tremor, where most have demonstrated that the best effect is
achieved from contacts outside the thalamic target, in the PSA. Concerning other
targets/indications the literature is even more limited.
The existing studies are further hampered by the heterogeneity of the methods. Often it is
not the actual location of the electrode that is reported, but the intended one. Even when
the actual location is reported it is most often presented according to distant landmarks,
even if the targeting was done visually, which is a significant problem, taking into
consideration the inter-individual variability. Further, even though the stimulation
parameters used can differ widely and hence the electrical current affect different
neighboring structures, this is virtually never taken into account.
DBS for ET - Conclusions and aim DBS for ET is thus not an evidence based therapy and the
same is true regarding both target areas used for ET. The relative merits of the different
targets used have not been clearly demonstrated and the individual targets are not well
delineated. There is thus a need to address these issues.
Overview - What are we going to study? The effect of DBS for ET will be evaluated in a
multicentre study recruiting 100 patients randomized to immediate surgery (group A) or best
medical treatment only (as decided by the movement disorder neurologist, with few exceptions
likely to be identical to their current medication) with delayed surgery at 6 months if still
needed /indicated (group B). Primary outcome is tremor reduction as measured with Essential
tremor rating scale11 (ETRS), with focus on items 5/6 (hand tremor) & 11-14 (hand function),
at baseline before surgery and at 6 months. Secondary outcome includes the essential tremor
rating assessment scale (TETRAS), quality of life measured with QUEST and electrical energy
consumption18. After 6 months group B is operated -as indicated-, and group A and B are
thereafter evaluated as one single group for long-term effects and analyses of electrode
location. The electrodes will in all patients be inserted with a trajectory developed for
this study allowing stimulation both in the established and traditionally used target Vim as
well as in the new target cZi. Each contact will be evaluated individually concerning
location, effects and side effects, in relation to stimulation parameters. This is done in
order to, a) compare the two targets, but more importantly, b) to create a map of the whole
area with identification/delineation of the optimal target point/volume. The time necessary
to gather 100 patients is estimated to 2.5 - 3 years.
Study design:
- Step 1 is designed as a randomized controlled trial in order to compare the effect of
DBS (Group A) and medical treatment (Group B) on ET (Aim 1).
- In step 2 - 4 the patients in group A are operated and group A and B joined into one
single group.
- Step 2 - all electrode contacts are individually analysed regarding chronic and
acute stimulation effects in relation to their location in either the Vim or the
cZi in order to decide which target is more effective (Aim 2).
- Step 3 - Effects and side effects, with consideration to field of stimulation, are
analyzed in relation to neighboring structures in order to map the whole area and
delineate the optimal target points (Aim 3).
- Step 4 - The long-term effect is evaluated in a non-randomized longitudinal study
at 1, 3, 5, 10 years (Aim 4).
Sample size and power:
In step 1, with a confidence interval of 95%, and an expected improvement of 85 % in the
surgical group and none (or at least < 25%) in the medical group, regarding contralateral
items 5/6 & 11-14, a power of 100 % is achieved. In step 2, with an expected improvement of
85% in one target and 60% in the other, a power of 98% is achieved. The high number of
patients is, however, necessary for step 3, mapping of the area, in order to give a good
cover of the periphery (Length of contact carrying electrode surface 7.5 mm, expected mean
non-random intended deviation from target point (as defined in the study) 1 mm, expected mean
random deviation from intended target point 1.5 mm). Based on the previous experience, less
than 5% of patients is expected to be lost during the follow up, which will have an
insignificant effect on the power.
